Tissue-Adhesive Material

ABSTRACT

The invention is directed to a tissue-adhesive polymer blend comprising a bioresorbable carrier polymer and a bioresorbable synthetic tissue-reactive polymer as well as to a tissue-adhesive device for sealing dura mater comprising said tissue-adhesive polymer blend.

The invention is in the field of bioresorbable adhesive materials formedical applications. In particular, the invention is directed to atissue-adhesive polymer blend and devices comprising such a blend, whichare used for sealing dura mater.

Tissue-adhesive materials are used in a variety of medical applications.These materials are for instance used to cover or seal wounds to preventor reduce leakage of bodily fluids. A particular application fortissue-adhesive materials is the sealing of dura mater. Dura mater isthe outermost membrane layer that surrounds the brain and spinal cord ofthe central nervous system. After e.g. trauma or cranial surgery, openeddura mater needs to be sealed to prevent leakage of cerebrospinal fluid.Even when in an operation dura mater is closed by suture, staples andsuch, cerebrospinal fluid may still leak, in particular throughremaining small openings. It is therefore typically required that thedura mater is sealed by a surgical sealant. Preferably, this sealantmaterial is based on a tissue-adhesive material such that no glue orother type of adhesive is required to apply the sealant and seal thedura mater.

It is desired that the tissue-adhesive material is characterized by anumber of properties. The tissue-adhesive bioresorbable material shouldbe biocompatible meaning that it is non-toxic and cause minimalinflammatory and/or immune response. It is further preferred that thetissue-adhesiveness does not have irritating effect and/or inhibit thehealing process of the tissue. This biocompatibility may inter alia beachieved by a bioresorbable nature of the material. Bioresorbability inthis respect means that the material can be broken down by, and becleared from the body and does not require mechanical removal. Thebreakdown of the materials typically occurs through hydrolysis orenzymatic cleavage into smaller compounds that may be metabolized orexcreted, for instance via the kidneys or liver.

It is further required that the device has a sufficient adhesivestrength to dura mater. Additionally, the device is preferablysufficiently burst-resistant, preferably for the entire period that isrequired for the dura mater to heal and close. Sufficient adhesivestrength and burst resistance are prerequisites for appropriate sealingof dura mater. Moreover, it is preferred that the device is appliedeasily by a surgeon during surgery.

Some known tissue-adhesive dura sealants are based on in situ hydrogelformation (e.g. DuraSeal™). These hydrogel-forming materials aretypically based on a two-component system of which the components areseparately but simultaneously applied on the tissue to be sealed. Thetwo components then form a hydrogel on the surface of the tissue therebysealing it. A drawback of such two-component based system is thedifficult handling of systems during surgery. Moreover, since thelifetime of the hydrated components is limited, two-component systemstypically have to be freshly prepared (hydrated) before use.Additionally, hydrogels such as DuraSeal™ are associated withpost-operative swelling with the risk of post-operative compression ofe.g. the spinal cord (see e.g. Lee et al., Korean Journal Spine 10(March 2013) 44-46).

A tissue-adhesive device is disclosed in WO2011/079336 and availableunder the trade name Hemopatch™. A drawback of this patch is its smalladherence strength towards dura mater making it ineffective in sealingdura mater.

WO2009/019516 discloses another tissue-adhesive device available underthe trade name TissuePatchDural™. Drawbacks of TissuePatchDural™ are itslow adherence strength to dura mater and limited durableburst-resistance meaning that its (dura mater) sealant properties arereduced over time and typically lost within 24 hours. Moreover, thepoly(acrylic acid) based polymers from which the patch is made are onlylimited bioresorbable.

The present inventors have found a polymer blend that can be used forthe production of a tissue-adhesive device that accommodates the aboveproperties and at least partially solves the drawbacks of the knowntissue-adhesive devices. The present invention thus provides atissue-adhesive polymer blend comprising a bioresorbable carrier polymerand a bioresorbable synthetic tissue-reactive polymer.

The carrier polymer is present in the blend to provide structuralsupport to the device that comprises the polymer blend. Suitable carrierpolymers may be synthetic or biological.

Preferably, a synthetic carrier polymer comprises polyesters,polyethers, polyhydroxyacids, polylactones, polyetheresters,polycarbonates, polydioxanes, polyanhydrides, polyurethanes,polyester(ether)urethanes, polyurethane urea, polyamides,polyesteramides, poly-orthoesters, polyaminoacids, polyphosphonates,polyphosphazenes and combinations thereof. Preferably, the syntheticcarrier polymer consists of polyesters and/or polyethers. Preferredpolyesters are based on lactide (D and/or L), ε-caprolactone, glycolideand combinations thereof.

Particular good results have been achieved with the synthetic carrierpolymer that comprises a poly(DL-lactide-co-ε-caprolactone) copolymerobtainable by the copolymerizaton of DL-lactide and ε-caprolactone,which copolymer preferably has a lactide content of 51-75 mol %, morepreferably of 55-70 mol %, most preferably of 62-69 mol %. In aparticular embodiment, the polyester such aspoly(DL-lactide-co-ε-caprolactone) copolymer, is a block (or segment) ofa larger polymer, such as a block in polyurethanes as disclosed inWO99/64491 and WO2004/062704 (which are both incorporated herein intheir entirety).

It is preferred that the synthetic carrier polymer is thepoly(DL-lactide-co-ε-caprolactone) copolymer. This copolymer isdisclosed in e.g. WO2003/066705 (which is incorporated herein in itsentirety).

In the embodiment wherein the carrier polymer is biological, thebiological carrier polymer typically comprises a polysaccharide that ispreferably selected from the group consisting of amylose, amylopectineand/or glycogen. Particular good results have been achieved withamylopectine which is thus preferred for the biological carrier polymer.

Advantageously, the synthetic carrier polymer makes it possible toeasily vary the structure of the device (i.e. for instance a foam, gelor sheet may be formed). Moreover the bioresorbability of the syntheticcarrier polymer can be modified by variation of the chemicalcomposition.

The tissue-adhesive properties of the polymer blend originate inter aliafrom the tissue-reactive polymer that comprises a tissue-reactive group.With tissue-reactive functional group is meant any chemical group,functionality or moiety that may react with tissue and form a covalentbond. Cells (and thus the tissue that is formed by cells) typicallycomprises protein and carbohydrates on the outer surface that may reactin a variety of reactions. The present invention is thus based on theidea that the tissue-reactive polymer reacts with the tissue and acovalent bond is formed. For instance, amines of proteins may react withactivated ester to form amide bonds or a sulfide may react with anothersulfide to form a disulfide bond. It may be appreciated that otherbonding types, such as Van-der-Waals interactions, hydrogen bonding,ionic interaction and the like, may also play a role in the overallbonding capacity of the tissue-reactive polymer of the presentinvention. The specific occurrence and strength of each type of bondinggenerally depends on the type of tissue, the chemical composition of thetissue-reactive polymer and the structure of the device based thereon.

The tissue-reactive functional group is appropriately stable in anaqueous environment, but at the same time sufficiently reactive withrespect to the tissue. Although the tissue-reactive functional group maybe sensitive to hydrolysis, appropriately stable means that the groupremains stable for a period long enough for the tissue-adhesive polymerto react with the tissue. As such, preferred tissue-reactive polymers inaccordance with the present invention comprise a tissue-reactivefunctional group that is an activated ester, an acid chloride, ananhydride, an aldehyde, p-nitrophenyl carbonate, epoxide, an isocyanate,vinyl sulfone, maleimide, o-pyridyl-disulfide, a thiol or combinationsthereof. Activated esters, acid chlorides, anhydrides, aldehydes, vinylsulfone, maleimide and isocyanates are electrophilic groups that maytypically react with an amine or another nucleophile of the tissue.Thiol or o-pyridyl-disulfide may form a disulfide bond with the tissue.

Particularly preferred as the tissue-reactive functional group areactivated esters. The activated ester may be a thioester, aperfluoroalkyl ester, a pentafluorophenol ester, a N-hydroxysuccinimide(NHS) ester, derivatives thereof, as well as combinations of these.Particularly good results have been obtained with N-hydroxysuccinimideester, as this ester is stable enough to allow easy handling but alsoallows a good tissue-bonding. N-hydroxysuccinimide ester or derivativesthereof is therefore most preferred. Examples of derivatives of NHSester are N-hydroxysulfosuccinimide and salts thereof.

In a particularly preferred embodiment of the present invention, thetissue-reactive polymer is based on polyethylene glycol, preferablybased on a multi-arm polyethylene glycol (PEG), more preferably a 4-armor an 8-arm polyethylene glycol, most preferably an 8-arm polyethyleneglycol.

It was surprisingly found that in case the tissue-reactive polymer isbased on a multi-arm polyethylene glycol, the adhesive strengths of thetissue-reactive polymer to tissue, in particular to dura mater, isgreatly improved. Such an improved tissue-adhesive strength ofmulti-arm-PEG-based blends is observed even if the number oftissue-reactive groups per gram of the tissue-adhesive polymer blend islower compared to tissue-reactive polymer blends that are not based onmulti-arm PEG (e.g. linear PEG-based tissue-adhesive polymers). Using amulti-arm PEG based tissue-reactive polymer thus allows the use of lessof this polymer in the blend to obtain the same tissue-adhesive strengthor the use of a similar amount of this polymer in the blend to obtain ahigher tissue-adhesive strength when for instance compared to linearPEG-based tissue-adhesive polymers. There is thus a strong synergisticeffect between PEG-based tissue-adhesive polymers and the multiplicityof the arms of such polymers.

A multi-arm PEG is typically based on a core comprising multipleanchoring groups where polyethylene glycol arms or groups can be joined.Since the core is typically relatively small compared to the PEG arms,the multi-arm PEG may typically be regarded as star-shaped. However, thecore may also comprise a larger component such as a polymer (e.g.polyethylene glycol) and may thus also be of a considerable length andweight. A typically core for a 4-arm PEG may for instance be based onerythritol or pentaerythritol while a typically core for an 8-arm PEGmay for instance be based on hexaglycerol. The distal end of each arm istypically functionalized with a spacer that is functionalized with thetissue-reactive functional group.

The multi-arm PEG may be varied in terms of the composition of the core,arm length, spacer composition, spacer length and composition of thetissue-reactive functional group. The arms in a multi-arm PEG aretypically of about the same molecular weight (and thus size).

The tissue-reactive polymer preferably has a molecular weight of 2000 to100000 g/mol, preferably 10000 to 80000 g/mol, more preferably 20000 to60000 g/mol, most preferably about 40000 g/mol.

The tissue-reactive polymer is typically a complex compound thatrequires elaborative synthetic efforts and as such relatively expensivein comparison to the carrier polymer. It is therefore preferred to usethe minimal amount of tissue-reactive polymer required for an adequatetissue-adhesiveness of the polymer blend and/or the device thereof. Assuch, the ratio carrier polymer and tissue-reactive polymer in thematerial (calculated on the weight) is 1:10 to 10:1.

The more preferred ratio may depend on the application of the blend inthe device. For instance, the blend may be used in a single-layeredtissue-adhesive devices or in a multi-layered (e.g. bi-layered) device(vide infra). In the case that the tissue-adhesive device issingle-layered, the ratio carrier polymer tot adhesive polymer ispreferably 1:10, more preferably 1:5, most preferably 1:3. In case thetissue-adhesive device is multi-layered, the ratio carrier polymer toadhesive polymer may be 10:1, more preferably 5:1, most preferably 3:1.

In a preferred embodiment of the present invention, the tissue-adhesivepolymer blend further comprises a buffering agent, preferably abuffering agent having a pH of more than 7, more preferably in the rangeof 8 to 10. It was surprisingly found that the presence of the bufferingagent improved the tissue-adhesive properties of the tissue-adhesivepolymer blend. Without wishing to be bound by theory, the inventorsbelieve that the buffering agent provides locally a favorable(preferably elevated) pH-value under which the rate of the reaction ofthe tissue with the tissue-reactive polymer is higher.

The buffering agent is preferably not detrimental to the degradationproperties of the polymer blend. In addition, the buffering agent ispreferably biocompatible. Accordingly, the buffering agent is preferablyselected from the group consisting of phosphates (e.g. Na₂HPO₄),carbonates, acetates, citrates, Good's buffers (preferably thoseapplicable in a pH range of more than 7, more preferably more than 8)such as bicine and the like.

In a particular embodiment, additionally to the carrier polymer and thetissue-reactive polymer, a filler polymer may be present. The fillerpolymer is typically based on polyethylene glycol that is notfunctionalized with the tissue-reactive functional group. The functionof the filler polymer is to provide stiffness to the carrier polymer.

The tissue-adhesive polymer blend in accordance with the presentinvention may be for use in a method of surgery, in particular in amethod of sealing dura mater.

A further aspect of the present invention is directed to atissue-adhesive device for sealing dura mater comprising thetissue-adhesive polymer blend. The device may have a foam structure, asheet structure, a gel-like structure or combinations thereof.Particular good results have been obtained with a foam structure, whichis therefore preferred.

In a preferred embodiment of the device, a illustrated in FIGS. 1 and 2,the device comprises a foam layer (1) of the polymer blend which is areleast partially covered by sheet layer (2). It was found that the sheetlayer can provide additional resistance towards leakage and burst. It ispreferred that the sheet layer is colored differently than the foamlayer such that when in use, the tissue-adhesive (foam) layer can moreeasily be distinguished form the sheet layer.

The sheet layer may for instance comprise a polyester or a polyurethane.Preferably, the sheet layer comprises a polyurethane, more preferably apolyurethane based on diisocyanate linked polyester polymer and diolcomponents as described in WO99/64491. Most preferably, such apolyurethane is based on 50/50 D,L-lactide/ε-caprolactone copolyesterprepolymer (PP) end-capped with 4-butanediisocyanate and polymerizedwith a diol based on two 1,4-butane diol components (BDO) which arelinked by a 1,4-butanediisocyanate (BDI)—i.e. a polyurethane having astructure of (BDI-PP-BDI-BDO-BDI-BDO)_(n).

Preferably, the device or the above-described foam layer (1) consistessentially of the tissue-adhesive polymer blend.

Other components such as drugs (e.g. hemostatic, anti-inflammatoryagents and the like), may also be present in the device, as long asthese components do not undesirably interfere with the adhesiveproperties of the device.

Typically, the tissue-adhesive device has a multilayered structurecomprising at least two layers. A first layer comprises thetissue-adhesive polymer blend and a second layer essentially consistingof the carrier polymer optionally blended with the filler polymer. Thefirst layer will be applied to the dura mater for adhesion and thesecond layer will mainly provide support. In another embodiment, theconcentration of the tissue-reactive polymer varies gradually in thedirection perpendicular to the plane of the device that may adhere tothe dura mater. In such embodiments, the required amount oftissue-reactive polymer may be limited.

The inventors have found that the device in accordance with the presentinvention adheres surprisingly well to dura mater and bone tissue. Itwas furthermore found that adhesion of devices in general, thusincluding the devices known in the prior part, may vary depending on thetype of tissue to adhere to. For instance, a device adhering well toliver tissue may adhere only moderately to dura mater. It was found infact, that dura mater is particularly difficult to adhere to.

The device in accordance with the present invention preferably has anadhesive strength of more than 1.0 N. The adhesive strength isdetermined by slicing a piece of dura mater into two slices and adheringthe device to both slices such that the slices are joined at their pointof slicing to form a bond between the device and the dura mater. Byusing a universal testing machine, the joined slices are pulled apart at10 mm/min to determine the maximum load applied before failure of thebond between the device and the dura mater. The adhesive strength isdefined as the maximum load applied before failure of the bond betweenthe device and the dura mater.

Preferably, the device remains adhesive to the dura mater for aprolonged period of time, sufficient for the dura mater to heal and toclose. At the site of the wound, moist conditions are commonlyencountered. As such, the device preferably has a durable adhesivestrength of more than 1.0 N for at least 24 hours under wet conditions.The durable adhesive strength is determined similarly to the adhesivestrength, with the difference that the slices joined by the adheringdevice are submerged and stored in a saline solution for a certain timeperiod before the breaking point of the bonding of the device with thedura mater is determined. Most preferably, the device has a durableadhesive strength of more than 1.0 N for at least 1 week.

Dura mater typically experiences a pressure of 8-15 mm Hg from thecerobrospinal fluid. Major peak pressures of 70 mmHg, albeit very short,may be experienced due to hiccups, sneezing, coughing and the like. Thedevice in accordance to the present invention therefore preferably has aburst-resistance of at least 8 mmHg, preferably at least 15 mmHg, morepreferably at least 30 mmHg, most preferably at least 45 mmHg.

The burst-resistance is determined by closing a container containing aliquid with dura mater. The dura mater is punctured such that a puncturewith a diameter of about 3 mm is obtained. The puncture is covered withthe device that adheres to the dura mater surrounding the puncture byapplying a force of 9.8N for 2 minutes. Then, the pressure in thecontainer is increased such that the liquid contained in the containedexerts a pressure on the device sealing the puncture. Theburst-resistance is the point at which leakage occurs.

Preferably, the device remains burst-resistant to the dura mater for aprolonged period of time, sufficient for the dura mater to heal and toclose. As such, the device preferably has a durable burst-resistance ofat least 8 mmHg, preferably at least 15 mmHg for at least 24 hours. Thedurability of the burst-resistance is determined similarly to theburst-resistance, with the difference that the punctured dura matersealed by the device is submerged and stored in a saline solution for acertain time period before the bursting point of the device isdetermined. Most preferably, the device has a durable burst-resistanceof more than 15 mmHg for at least 1 week.

For the purpose of clarity and a concise description features aredescribed herein as part of the same or separate embodiments, however,it will be appreciated that the scope of the invention may includeembodiments having combinations of all or some of the featuresdescribed.

The invention may be illustrated with the following examples.

EXAMPLE 1: PREPARATION OF POLYESTER FOAM DEVICE

A device based on a polymer blend comprisingpoly(DL-lactide-co-ε-caprolactone) copolymer and tissue-reactive polymer8-arm NHS-functionalized PEG of 40 kD with a glutarate spacer(8APEGNHS40k) was prepared as follows.

Poly(DL-lactide-co-ε-caprolactone) copolymer (LLC) was prepared bycopolymerization of DL-lactide and ε-caprolactone as described inWO2003/066705. 8APEGNHS40k was purchased from Jenkem Technologies.

The copolymer was dissolved in dioxane in a concentration of 2.5 wt %with cyclohexane (2 wt %) as porogen. 8APEGNHS40k was added to yieldconcentration of 50 mg/mL. The solution was poured in a mold (2×2×1.5cm)_and cooled at −24 C. Freeze-drying of the solidified solutionsprovided the foam device. In another example molds of 5×5 cm and 10×10cm were used with the appropriate amount of the solutions.

EXAMPLE 2: PREPARATION OF A MULTILAYERED POLYESTER FOAM DEVICE

A solution is prepared according to Example 1, 1 mL from this solutionis poured in a mold (2×2×1.5 cm) and the mold is subsequently cooled(−24° C.) until the solution has solidified. On top of the frozensolution 1 mL of a second solution containing PEG-OH (20 k) in1,4-dioxane (conc.) is added. The mold is placed at −24° C. until theentire content of the mold has solidified. The mold is placed in thefreeze-dryer and the solvent is removed overnight.

EXAMPLE 3: PREPARATION OF A POLYESTER FOAM DEVICE WITH A DENSE SHEET ONONE SIDE

A solution of polyurethane (about 2 wt %) in chloroform is cast in amold as described in example 2. After evaporation of the solvent a sheetis obtained. The mold and the sheet are cooled at −24° C.

The LCC copolymer of Example 1 was dissolved in dioxane in aconcentration of 2.5 wt % with cyclohexane (2 wt %) as porogen.8APEGNHS40k was added to yield concentration of 50 mg/mL. The solutionwas poured on top of the cooled sheet in the mold (2×2×1.5 cm) andsubsequently cooled at −24 C. Freeze-drying of the solidified solutionsprovided the foam device. In other examples molds of 5×5 cm and 10×10 cmwere used with the appropriate amount of the solutions.

EXAMPLE 4: PREPARATION OF A POLYESTER FOAM DEVICE WITH A SHEET ON ONESIDE AND CONTAINING BUFFER SALT

A solution of polyurethane (about 3 wt %) in chloroform was cast in amold. After evaporation of the solvent a sheet was obtained. The moldand the sheet were cooled at −24° C.

The LCC copolymer of Example 1 was dissolved in dioxane in aconcentration of 2.5 wt %. 8APEGNHS40k was added to yield concentrationof 40 mg/mL. To this, disodium hydrogen phosphate was added in 3 mg/mLconcentration. The obtained solution was poured on top of the cooledsheet in the mold (7×7×1.5 cm) and subsequently cooled at −24 C.Freeze-drying of the solidified solutions provided the foam device.

EXAMPLE 5: PREPARATION OF AMYLOPECTINE FOAM DEVICE

Amylopectine was mixed with water in a ratio of 1:7 by weight. Byheating the suspension (95° C.) under vigorous stirring for 60 minutes agel was obtained. The gel was poured in a mold (2×2×1.5 cm), cooled(−24° C.) and after freeze-drying a foam of amylopectine was obtained.

EXAMPLE 6 AMYLOPECTIN FOAM DEVICE IMPREGNATED WITH 8APEGNHS COVERED WITHCOPOLYESTER SHEET

A foam of amylopectin prepared according to example 5 was impregnatedwith a solution of tissue reactive polymer (8APEGNHS10k) in chloroform.To obtain a loading of 80 mg tissue reactive polymer in the foam. Afterevaporation of the solvent the foam is covered with a sheet ofcopolyester poly(DL-lactide-co-ε-caprolactone) copolymer.

The sheet of the poly(DL-lactide-co-ε-caprolactone) copolymer is coveredwith a 2 wt % solution of the copolymer in chloroform and theamylopectine foam with tissue reactive polymer is pressed on the sheet.After evaporation of the solvent a foam with a dense sheet on top isobtained.

EXAMPLE 7: DETERMINATION OF ADHESIVE STRENGTH

The adhesive strength of is determined by slicing a piece of porcinedura mater into two slices and adhering the device to both slices suchthat the slices are joined at their point of slicing. Adherence isachieved by applying a force of 9.8 N for 2 minutes.

By using a universal testing machine, the joined slices are pulled apartat 10 mm/min to determined the force required to break the bonding ofthe device with the dura mater. The adhesive strength is defined as themaximum load before failure of the bond between the device and the duramater.

COMPARATIVE EXAMPLE 1: DETERMINATION OF ADHESIVE STRENGTH OFCOMMERCIALLY AVAILABLE SEALANTS

In a comparative example, the adhesive strength of commerciallyavailable sealants are determined as described in example 7. The resultsare provided in Table 1.

TissuePatchDural™ is commercially available from Tissuemed, Hemopatch™and TachoSil™ are commercially available from Baxter.

TABLE 1 Device Adhesive strength (N) Example 1 (LCC + 8APEGNHS40k) 1.373Example 2 multilayered device 1.560 Example 4 (LCC/8APEGNHS40k/ 6.9Na₂HPO₄ buffer) + copolyurethane sheet Example 5 amylopectin device 0.13Example 6 (amylopectin/8APEGNHS10k) + 1.824 copolyester sheetComparative examples TissuePatchDural ™ 0.439 Hemopatch ™ 0.487Tachosil ™ 0.850

EXAMPLE 8: DETERMINATION OF DURABLE ADHESIVE STRENGTH

Devices given in table 2 were prepared comparable to example 1, but withtissue-reactive polymers with a different number of arm and a differentmolecular weight.

The durable adhesive strengths of the devices were tested in a methodcomparable to example 7, with the difference that the slices joined bythe adhering device are submerged and stored in a saline solution for acertain time period (0-168 h, as indicated in table 2) before theadhesive strength of the device with the dura mater is determined. Theresults are given in table 2.

TABLE 2 Devices Comp. Time LCC + LCC + LCC + device (h) 8APEGNHS40k4APEGNHS10k 8APEGNHS10k Tachosil 0 1.37 0.98 0.7 0.85 24 2.44 0 96 2.171.71 1.02 0 168 1.61 1.74 1.46 0

EXAMPLE 9: DETERMINATION OF ADHESIVE STRENGTH DEPENDENT IN PEG MULTI-ARMBASED DEVICES

Three different devices (devices #1-3), each comprising the sameconcentration of a different tissue-adhesive polymer having aNHS-comprising PEG arms were provided as described in Example 1.

The adhesive strength of each device on dura mater was determined asdescribed in Example 7.

-   -   Device #1-1 arm: 1PEGNHS2k (1 mmol NHS per gram polymer)    -   Device #2-4 arms: 4PEGNHS10k (0.4 mmol NHS per gram polymer)    -   Device #3-8 arms: 8PEGNHS40k (0.2 mmol NHS per gram polymer)

The adhesive strength is provided in FIG. 3. The results show that,despite less NHS per gram of polymer, multi-arm PEG tissue-adhesivepolymer devices demonstrate a relatively high adhesive strength to duramater.

EXAMPLE 10: BURST-RESISTANCE

The burst-resistance of devices obtained from examples 1 and 2 weredetermined by closing a container containing a liquid with dura mater.The dura mater is punctured such that a puncture with a 3 mm diameter isobtained. The puncture is covered with the device that adheres to thedura matter surrounding the puncture by applying a force of 9.8 N for 2minutes. Then, the pressure in the container is increased such that theliquid contained in the contained exerts a pressure on the devicesealing the puncture. The burst-resistance is the point at which thedevice bursts.

Results are provided in table 3.

COMPARATIVE EXAMPLE 2: BURST-RESISTANCE OF COMMERCIALLY AVAILABLESEALANTS

In a comparative example, the burst-resistance of commercially availablesealants are determined as described in example 10. The results areprovided in Table 3.

TABLE 3 Device burst-resistance (mmHg) Example 1 LCC + 8APEGNHS40k 59Example 1 LCC + 8APEGNHS40k 16 (after 24 h in saline) Example 4 (LCC +8APEGNHS40k + 106 Na₂HPO₄ buffer) + copolyester sheet Example 5Amylopectine 14 Example 6 (amylopectin/8APEGNHS10k) + 51 copolyestersheet Comparative devices Hemopatch ™ 19 TissuePatchDural ™ 7

EXAMPLE 11: EFFECT OF BUFFER ON DEGRADATION OFPOLY(DL-LACTIDE-CO-ε-CAPROLACTONE) COPOLYMER (LLC)

The poly(DL-lactide-co-ε-caprolactone) copolymer (LLC) as prepared inExample 1 was dissolved in dioxane in a concentration of 2.5 wt and oneof three different buffer solutions (phosphate, bicine, carbonate) wasadded in 3 mg/mL concentration. The obtained solution cooled at−24 C andfreeze-dried to provided the foam device.

The foam device was placed in a physiological solution at 40° C., 80%relative humidity and the degradation of the LCC copolymer was monitoredin time.

The results are provided in FIG. 4. The presence of the buffer in thefoam does not have a detrimental negative effect on the degradation ofthe foam.

1.-17. (canceled)
 18. A tissue-adhesive polymer blend comprising abioresorbable carrier polymer and a bioresorbable synthetictissue-reactive polymer, wherein the synthetic tissue-reactive polymeris based on a multi-arm polyethylene glycol and is functionalized withat least one tissue-reactive group that comprises an activated ester,wherein the tissue-reactive polymer has a molecular weight of 20000g/mol or more.
 19. Tissue-adhesive polymer blend according to claim 18,wherein the carrier polymer is a synthetic carrier polymer comprisingpolyesters, polyethers, polyhydroxyacids, polylactones, polyetheresters,polycarbonates, polydioxanes, polyanhydrides, polyurethanes,polyester(ether)urethanes, polyurethane urea, polyamides,polyesteramides, poly-orthoesters, polyaminoacids, polyphosphonates,polyphosphazenes and combinations thereof.
 20. Tissue-adhesive polymerblend according to claim 19, wherein the synthetic carrier polymercomprises a poly(DL-lactide-co-ε-caprolactone) copolymer obtainable bythe copolymerizaton of DL-lactide and ε-caprolactone. 21.Tissue-adhesive polymer blend according to claim 18, wherein the carrierpolymer is a biological polymer comprising a polysaccharide. 22.Tissue-adhesive polymer blend according to claim 18, wherein theactivated ester is selected from the group consisting of a thioester, aperfluoroalkyl ester, pentafluorophenol ester, N-hydroxysuccinimideester and derivatives thereof.
 23. Tissue-adhesive polymer blendaccording to claim 18, wherein the tissue-reactive polymer is based on a4-arm or an 8-arm polyethylene glycol.
 24. Tissue-adhesive polymer blendaccording to claim 18, wherein the tissue-reactive polymer has amolecular weight of up to to 100000 g/mol.
 25. Tissue-adhesive polymerblend claim 18, wherein the weight ratio of the carrier polymer to thetissue-reactive polymer in the material is 1:10 to 10:1. 26.Tissue-adhesive polymer blend according to claim 18, further comprisinga filler polymer that is typically based on polyethylene glycol that isnot functionalized with the tissue-reactive functional group. 27.Tissue-adhesive polymer blend according to claim 18, further comprisinga buffering agent which is preferably selected from the group consistingof phosphates, carbonates, acetates, citrates, Good's buffers andcombinations thereof.
 28. (canceled)
 29. Tissue-adhesive device forsealing dura mater comprising the tissue-adhesive polymer blend inaccordance to claim 18, preferably having a foam structure, a sheetstructure, a gel-like structure or combinations thereof. 30.Tissue-adhesive device for sealing dura mater according to claim 29comprising a foam structure.
 31. Tissue-adhesive device for sealing duramater according to claim 29, having a multilayered structure comprisingat least two layers of which a first layer which comprises a foamstructure that comprises a tissue-adhesive polymer blend in accordanceto claim 18 and a second layer which comprises a sheet structure. 32.Tissue-adhesive device for sealing dura mater according to claim 29,having a multilayered structure comprising at least two layers of whicha first layer comprises a tissue-adhesive polymer blend in accordance toclaim 18 and a second layer essentially consisting of the carrierpolymer in accordance to claim
 18. 33. Tissue-adhesive device forsealing dura mater according to claim 29, having an adhesive strength ofmore than 1 N.
 34. Tissue-adhesive device for sealing dura materaccording to claim 29, having a burst-resistance of at least 8 mmHg. 35.Tissue-adhesive device for sealing dura mater according to claim 29,having a burst-resistance of at least 15 mmHg.
 36. Tissue-adhesivedevice for sealing dura mater according to claim 29, having aburst-resistance of at least 30 mmHg.
 37. Tissue-adhesive device forsealing dura mater according to claim 29, having a burst-resistance ofat least 45 mmHg.
 38. Tissue-adhesive polymer blend according to claim24, wherein the tissue-reactive polymer has a molecular weight of up toto 80000 g/mol.
 39. Tissue-adhesive polymer blend according to claim 24,wherein the tissue-reactive polymer has a molecular weight of 20000 to60000 g/mol.
 40. Tissue-adhesive polymer blend according to claim 27,wherein the buffering agent is selected from the group consisting ofphosphates, carbonates, acetates, citrates, Good's buffers andcombinations thereof.
 41. Method for sealing dura mater of the humanbody by sealing the dura mater with a tissue-adhesive polymer blend inaccordance with claim 18.